My topic for the research paper is the molecular pathogenesis of Alzheimer's Disease
Summary of Article
Article: Current theories for the molecular and cellular pathogenesis of Alzheimer's disease (Gunnar K. Gouras)
Expert Reviews in Molecular Medicine / Volume 3 / 2001, pp 1-11, DOI: http://dx.doi.org/10.1017/S1462399401003167
Introduction
Alzheimer's disease (AD) is the most common form of neurodegenerative disease.
Many researchers in the past decade have been researching on how the disease progresses.
There is still no definite answer about the pathogenesis but there are many hypotheses that have been made.
Defining features AD
AD was discovered by Alois Alzheimer.
Early on Alzheimer observed that there were two types of lesions that were connected to AD which were senile plaques and neurofibillary tangles using a newly developed silver stain.
In the mid-1980s, it was discovered that the beta-amyloid (Ab) protein is the main protein found in senile plaques.
This then led to cloning and biological studies that provided information on the intercellular formation of Ab.
It was discovered that the Ab was produced from the cleavage of Ab precursor protein (bAPP) by beta and gamma secretases.
In the early 1990s it was discovered that normal cells secrete Ab as well.
Hypotheses for the pathogenesis of AD
This hypothesis received support when early-onset familial AD is due to specific mutation in bAPP.
For the more common AD, late-onset, is mutation in the apolipoprotein E e4 allele.
Amyloid cascade is based on the neurotoxic properties of Ab. When Ab is produced easily aggregates to plaque and makes its surrounding toxic for neurons to function.
Current studies are trying to determine the molecular mechanism which ApoE influence Ab in AD.
The amyliod cascade can answer a lot of about the mechanism but it does not take into account how age influences these changes in normal cellular function?
How Ab leads to cell death of neurons and neuronal dysfunction?
Are there othere stress that can affect production of Ab?
Cardiovascular and cholesterol hypotheses
There have been studies that have linked cardiovascular factors to the development of AD.
There have been studies that showed that cholesterol depletion can lead to lower levels of Ab.
This is due to the fact that cholesterol affects the thickness and fluidity of the cell membrane. The cell membrane is where a critical cleavage step of Ab occurs. Therefore depending of the cell membrane it influences the site of cleavage.
Oxidative stress
In many other age-related diseases, oxidative stress and changes in energy metabolism play a pivotal role on how they progress.
Free radicals are produced during metabolism and can cause damages to proteins, lipids and nucleic acids which may cause mutation that may allow the higher level of Ab and the progression of AD.
Inflammation/Immune Responses
There have been studies that suggested that taking anti-inflammatory medication that can protect from the development of AD.
In AD pathology, inflammatory processes recruit inflammatory proteins to the site where Ab are deposited.
Hormones
Many epidemiological studies have suggested that estrogen affects the development of AD.
Estrogen replacement therapy showed that it delayed the development of AD in women with early to moderate AD.
Recently, it has shown that levels of bio-available testosterone decreases with age and has been shown to reduce the secretion of Ab.
Insulin is an important hormone in learning and memory.
Research has shown that insulin in the brain inhibits the phosphorylation of protein known as tau which is a component of neurofibillary tangles.
Other Hypothesis
There are many other hypotheses that have been proposed for the progression and cause of AD.
Activation of apoptosis and alteration of calcium flux in neurons bAPP physiological role has been altered to cause neuronal dysfunction
Low levels of acetylcholine, an important neurotransmitter of learning and memory can be another factor that causes the progression of AD.
My topic for the research paper is the molecular pathogenesis of Alzheimer's Disease
Summary of Article
Article: Current theories for the molecular and cellular pathogenesis of Alzheimer's disease (Gunnar K. Gouras)
Expert Reviews in Molecular Medicine / Volume 3 / 2001, pp 1-11, DOI: http://dx.doi.org/10.1017/S1462399401003167
Introduction
- Alzheimer's disease (AD) is the most common form of neurodegenerative disease.
- Many researchers in the past decade have been researching on how the disease progresses.
- There is still no definite answer about the pathogenesis but there are many hypotheses that have been made.
Defining features AD- AD was discovered by Alois Alzheimer.
- Early on Alzheimer observed that there were two types of lesions that were connected to AD which were senile plaques and neurofibillary tangles using a newly developed silver stain.
- In the mid-1980s, it was discovered that the beta-amyloid (Ab) protein is the main protein found in senile plaques.
- This then led to cloning and biological studies that provided information on the intercellular formation of Ab.
- It was discovered that the Ab was produced from the cleavage of Ab precursor protein (bAPP) by beta and gamma secretases.
- In the early 1990s it was discovered that normal cells secrete Ab as well.
Hypotheses for the pathogenesis of AD- This hypothesis received support when early-onset familial AD is due to specific mutation in bAPP.
- For the more common AD, late-onset, is mutation in the apolipoprotein E e4 allele.
- Amyloid cascade is based on the neurotoxic properties of Ab. When Ab is produced easily aggregates to plaque and makes its surrounding toxic for neurons to function.
- Current studies are trying to determine the molecular mechanism which ApoE influence Ab in AD.
- The amyliod cascade can answer a lot of about the mechanism but it does not take into account how age influences these changes in normal cellular function?
- How Ab leads to cell death of neurons and neuronal dysfunction?
- Are there othere stress that can affect production of Ab?
Cardiovascular and cholesterol hypotheses- There have been studies that have linked cardiovascular factors to the development of AD.
- There have been studies that showed that cholesterol depletion can lead to lower levels of Ab.
- This is due to the fact that cholesterol affects the thickness and fluidity of the cell membrane. The cell membrane is where a critical cleavage step of Ab occurs. Therefore depending of the cell membrane it influences the site of cleavage.
Oxidative stress- In many other age-related diseases, oxidative stress and changes in energy metabolism play a pivotal role on how they progress.
- Free radicals are produced during metabolism and can cause damages to proteins, lipids and nucleic acids which may cause mutation that may allow the higher level of Ab and the progression of AD.
Inflammation/Immune Responses- There have been studies that suggested that taking anti-inflammatory medication that can protect from the development of AD.
- In AD pathology, inflammatory processes recruit inflammatory proteins to the site where Ab are deposited.
Hormones- Many epidemiological studies have suggested that estrogen affects the development of AD.
- Estrogen replacement therapy showed that it delayed the development of AD in women with early to moderate AD.
- Recently, it has shown that levels of bio-available testosterone decreases with age and has been shown to reduce the secretion of Ab.
- Insulin is an important hormone in learning and memory.
- Research has shown that insulin in the brain inhibits the phosphorylation of protein known as tau which is a component of neurofibillary tangles.
Other Hypothesis